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D L Bellinger

Publications and source records attributed to D L Bellinger.

At least 37 records · Page 2Linked to original sources
PubMed1992

A longitudinal study of age-related loss of noradrenergic nerves and lymphoid cells in the rat spleen.

A longitudinal study of sympathetic noradrenergic (NA) innervation of the spleen was carried out in 3-, 8-, 12-, 17-, 21-, and 27-month-old Fischer 344 (F344) rats using (i) fluorescence histochemistry for localization of norepinephrine (NE); (ii) immunocytochemistry (ICC) for localization of tyrosine hydroxylase (TH)-positive nerve fibers alone, and in combination with specific markers for T and B lymphocytes (OX19 and anti-mu respectively), and macrophages (ED3); and (iii) high-performance liquid chromatography with electrochemical detection for quantitation of NE. Fluorescence histochemistry revealed extensive loss of NA nerve fibers in all compartments of the spleen in 21- and 27-month-old rats. With single-label ICC, a decline in TH+ nerve fibers in all compartments of the spleen was observed by 17 months of age and became more severe with advancing age; these findings suggest that both the rate-limiting enzyme and the transmitter itself (NE) are depleted from sympathetic nerves in aged rat spleen. Double-label ICC demonstrated the loss of TH+ nerve fibers in spleen from 17-, 21-, and 27-month-old rats, and a parallel loss of OX19+ T lymphocytes and ED3+ macrophages in these cellular compartments. Neurochemical measurement of NE demonstrated a decline in NE per wet weight at 27 months of age. The age-related decline in NA innervation of spleen and in the density of specific populations of cells of the immune system (T lymphocytes and antigen-presenting ED3+ macrophages), that follow remarkably similar time courses, supports functional evidence for dynamic interactions between the immune system and NA sympathetic nerves in the spleen, and further suggests a causal relationship between these age-related phenomena, i.e., that age-related immunosenescence promotes sympathetic denervation of the spleen which further compromises immune function. This hypothesis, however, requires further testing.

Aging↗
PubMed1992

Innervation of lymphoid organs and implications in development, aging, and autoimmunity.

We now have substantial evidence demonstrating noradrenergic sympathetic and peptidergic innervation of both primary and secondary lymphoid organs. We have established criteria for norepinephrine, and some of the neuropeptides, as neurotransmitters, and have found changes in immune responsiveness following pharmacological manipulation of noradrenergic sympathetic or peptidergic nerves. Classic receptor binding studies have demonstrated a wide variety of target cells that possess beta-adrenoceptors and receptors for neuropeptides on cells of the immune system, including lymphocyte subsets, macrophages, accessory cells, or stromal elements. In this chapter we describe noradrenergic and peptidergic innervation of primary and secondary lymphoid organs in development, at maturation and during the normal aging process, and discuss possible functional implications of direct neural signals onto cells of the immune system at critical time points in the lifespan of an animal. Further, we examine for involvement of noradrenergic sympathetic and peptidergic innervation in the development and progression of several autoimmune disorders, including adjuvant-induced arthritis, New Zealand mice strains as a model for hemolytic anemia and lupus-like syndrome, and the experimental allergic encephalomyelitis model for multiple sclerosis.

Adrenergic Fibers↗
PubMed1992

Noradrenergic and peptidergic innervation of secondary lymphoid organs: role in experimental rheumatoid arthritis.

Noradrenergic (NA) and peptidergic nerve fibres are present in both primary and secondary lymphoid organs, distributing with the vasculature, trabecular and capsular smooth muscle, and within the parenchyma among cells of the immune system. NA nerve terminals directly abut lymphocytes and macrophages in spleen and lymph nodes. In these organs, norepinephrine has fulfilled the basic criteria for neurotransmission with cells of the immune system as targets. In vitro and in vivo studies have demonstrated NA modulation of primary and secondary antibody responses, cytotoxic T cell responses, natural killer cell activity, and proliferation and differentiation of both T and B lymphocytes. Substance P (SP) has been shown to modulate inflammatory responses, lymphocyte proliferation, and other immunologic reactivity. We investigated the role of NA and SP nerve fibres within lymph nodes in experimental allergic auto-immune arthritis in Lewis rats. Denervation of NA nerve fibres in popliteal and inguinal lymph nodes with 6-hydroxy-dopamine resulted in earlier onset and enhanced severity of arthritic changes as well as inflammation in bilaterally induced experimental arthritis, while denervation of SP nerve fibres in popliteal and inguinal lymph nodes with capsaicin resulted in delayed onset and diminished severity of the inflammatory changes ipsilaterally, and prevention of contralateral arthritic changes in unilaterally induced experimental arthritis. These findings suggest that NA and SP nerve fibres in lymph nodes can modulate the time course of onset and the severity of experimental arthritis in Lewis rats. These modulatory effects are distinctly different from the effects of NA and SP nerve fibres in the joints themselves.

Animals↗
PubMed1991

Substance P innervation of spleen in rats: nerve fibers associate with lymphocytes and macrophages in specific compartments of the spleen.

We investigated the distribution of SP+ nerve fibers in the spleen of adult male Fischer 344 rats. SP+ nerve fibers entered the spleen with the splenic artery in the hilar region, arborized along the venous sinuses, and extended from these larger plexuses into trabeculae and the surrounding red pulp. In the white pulp, SP+ nerve fibers were found in the marginal zone, and in the outer regions of the PALS among T lymphocytes. No SP+ nerve fibers were observed in association with the splenic capsule, the central arteries of the white pulp, or the follicles. SP levels in rat spleen were 5.7 +/- 0.4 ng/g wet wt. On the basis of the present findings of SP presence in nerve fibers in the spleen, and published evidence for SP receptors on lymphocytes and macrophages, we suggest that SP derived from nerve fibers in the spleen can act as a neurotransmitter with cells of the immune system as targets. These SP nerve fibers may be an important neural link between the nervous system and the immune system and may participate in modulation of immune reactivity and inflammatory responses.

Animals↗
PubMed1990

Noradrenergic reinnervation of the rat spleen following chemical sympathectomy with 6-hydroxydopamine: pattern and time course of reinnervation.

The time course and pattern of reinnervation of noradrenergic (NA) sympathetic nerve fibers into the spleen following acute chemical sympathectomy with the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) was examined in young adult male Fischer 344 rats using glyoxylic acid fluorescence histochemistry and neurochemical measurement of NE. Reinnervation proceeds initially along the splenic artery as it enters the hilus (1-5 days), extends into the hilar region (5-10 days), and later proceeds into the regions distal to the hilus (21-56 days), suggestive of orderly growth from the hilar region to distal regions. In all 6-OHDA-treated spleens, the compartmentation of NA innervation was similar to that observed in saline-injected controls, but the density of NA nerve fibers in these compartments differed according to the distance from the hilus. By 56 days postlesion, regions distal to the hilar blood vessels contained fewer NA profiles than their age-matched controls, suggesting that the anatomical process of reinnervation does not restore the density of fibers in a fashion identical to that of nondenervated controls. In contrast, splenic NE concentration at 56 days postdenervation did not differ from the concentration seen in nondenervated control spleens. We suggest that functional restoration of splenic innervation may involve metabolic and receptor compensation for the lack of complete fiber regrowth into regions of white pulp distal from the hilus.

Adrenergic Fibers↗
PubMed1990

Fluorescence histochemical techniques for catecholamines as tools in neurobiology.

Formaldehyde-induced and glyoxylic-acid-induced fluorescence histochemistry permits the tissue localization of catecholamines in the central nervous system (CNS) and peripheral nervous system (PNS), and in culture. Counterstains such as ethidium bromide provide excellent background identification of specific innervated regions in both the CNS and the periphery. Use of fluorescence histochemistry with immunocytochemistry can elucidate catecholamine-peptide relationships. Gelatin-ink perfusion used with fluorescence histochemistry permits the investigation of neuro-vascular relationships and documentation of vascular and parenchymal compartmentation of innervation. Combined use of fluorescence histochemistry and retrograde tracing methods demonstrates the specific cellular sources of innervation of target regions. Micropunch neurochemical analysis provides quantitative data for correlation with fluorescence histochemistry within a target region of innervation, and microspectrofluorometric analysis provides a semi-quantitative evaluation of the amount of fluorophore within a target region or within specific subcellular compartments such as the cell body or terminals.

Animals↗
PubMed1989

Origin of noradrenergic innervation of the spleen in rats.

Noradrenergic (NA) sympathetic innervation of the spleen was examined in young adult Sprague-Dawley rats (200-250 g) following surgical removal of the superior mesenteric-celiac ganglia (SM-CG) and/or bilateral transection of the subdiaphragmatic vagus nerve. Sham-operated and unoperated rats served as controls. NA sympathetic innervation of spleens from sham-operated and unoperated controls, and from vagotomized rats, was qualitatively similar, with fibers distributing to the capsule, trabeculae, vasculature, and parenchyma of the white pulp. Complete ganglionic extirpation resulted in almost total denervation of NA fibers in all compartments of the spleen. High-performance liquid chromatography with electrochemical detection (LCEC) for catecholamines (CA) and quantitative morphometry of the density of NA varicosities confirmed these observations. LCEC revealed a greater than 85% depletion of norepinephrine (NE) in the spleen following superior mesenteric-celiac ganglionectomy. Stereological evaluation of NA varicosities with a point counting method revealed a decline of 99% in the volume density of NA terminals that occurred uniformly in all compartments of spleens from ganglionectomized rats. In addition, stereological analysis revealed a loss of total NA varicosities (approximately 31% decrease) in spleens from sham-operated rats. This loss in volume density occurred largely due to a loss in parenchymal fibers (approximately 45% decrease). Bilateral subdiaphragmatic vagotomy blocked the effect on NA innervation produced by the surgical stress of sham operation. Retrograde tracing following injection of either fluorogold or true blue into the spleen, coupled with immunocytochemical localization of tyrosine hydroxylase (TH), demonstrated abundant fluorogold (true blue)-labeled neurons in the SM-CG; many, but not all, of these neurons also were TH-positive. These findings indicate that the SM-CG neurons supply NA innervation to the spleen, providing sympathetic innervation as the second neuron in the classical two-neuron sympathetic chain, and suggest additional non-NA innervation of the spleen as well. This study also suggests that surgical stress of sham operation may alter directly the NA innervation of the spleen, possibly by inducing temporary retraction of NA fibers of the parenchymal compartment, which is likely to reduce the availability of NE for interaction with cells of the immune system that possess adrenoceptors and are present adjacent to NA varicosities in this region.4+ Bilateral vagotomy ameliorated the effects of sham operation on NA innervation; since the vagal nerve does not distribute fibers to the spleen, this effect is likely to occur through altered feedback circuits effecting sympathetic outflow, or through altered neuroendocrine outflow.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenergic Fibers↗
PubMed1988

Morphology of dendrite bundles in the cervical spinal cord of the rat: a light microscopic study.

Histological staining techniques and Golgi-Cox impregnation revealed three discrete dendrite bundles in the ventral horn of the rat cervical spinal cord. A midline dendrite bundle (MDB) traversed the ventromedial gray matter (C3-6), a central dendrite bundle (CDB) coursed the medial aspect of the ventral horn (C3-5), and a lateral dendrite bundle (LDB) traveled in the ventrolateral gray matter (C2-4). At the light microscopic level, the three dendrite bundles were composed of longitudinally oriented intertwined dendrites that coursed in close apposition among motoneuron perikarya, neuroglia, and capillaries. A gradient of packing density of dendrites in the bundles existed, the MDB displaying the greatest packing density and the LDB forming the most loosely interwoven dendritic plexus. Dendrites contributing to the bundles originated from several different motoneuron pools. Smaller transverse dendrite bundles radiated from the longitudinal dendrite bundles at right angles and appeared to interconnect the MDB, CDB, and LDB. Transverse dendrite bundles also exited the MDB and LDB to course into the anterior and lateral funiculi, respectively. The presence of dendrite bundles among fields of motoneurons suggests that dendrite bundles may provide an anatomical substrate for the synchronization of neuronal activity for coordination of muscle groups involved in particular movements. Dendrite bundles also would provide a means whereby functionally similar motoneurons can receive and integrate similar synaptic inputs, and thus allow these inputs to modulate and coordinate groups of neurons that act as a functional unit. The presence of transverse dendrite bundles interconnecting the longitudinal bundles may permit the fine tuning of motoneuron activity for better coordination of movements involving synergistic and antagonistic muscle groups.

Animals↗
PubMed1988

Maintenance of noradrenergic sympathetic innervation in the involuted thymus of the aged Fischer 344 rat.

Sympathetic postganglionic noradrenergic (NA) fibers innervate both primary and secondary lymphoid organs in the rat. In secondary lymphoid organs such as the spleen and lymph nodes, this innervation diminishes with age. This study was undertaken to determine whether a similar decline in NA innervation occurs in the thymus. Thymuses from Fischer 344 (F344) rats were examined at 3, 8, 12, 17, 21, and 27 months of age with fluorescence histochemistry for catecholamines, and with high-performance liquid chromatography with electrochemical detection (LCEC) for quantitation of monoamines. In adult animals of all age groups, the compartmentation of NA innervation was maintained; NA fibers entered the thymus with the vasculature and arborized in the cortex, particularly in the subcapsular region and around the vasculature at the corticomedullary junction. NA nerve fibers were sparse in the thymuses from 3-month-old rats and increased in density at 8 and 12 months of age. The density of NA nerve fibers in the thymuses from 17, 21, and 27 months of age increased further, in parallel with thymic involution. Quantitation of monoamines revealed stable thymic norepinephrine (NE) and 5-hydroxytryptamine (5-HT) content from 8 to 27 months of age. The lower levels of NE detected at 3 months of age may reflect a slow maturation and reorganization of this fiber system as a developmental phenomenon. Measurement of 3-methoxy-4-hydroxy-phenyleneglycol (MHPG), a major metabolite of NE, showed a more than twofold rise from 3 to 12 months of age, and remained high through 27 months of age. The resultant MHPG/NE ratios, as an index of NE availability for interaction with target cells, showed a decline from 3 months of age through 17-21 months of age, followed by a marked rise at 27 months of age. These findings suggest that the thymus is able to maintain NA innervation in the face of involution, and that these fibers provide a NA-enriched microenvironment for interaction with adrenergic receptors on thymocytes.

Adrenergic Fibers↗
PubMed1987

Noradrenergic sympathetic innervation of the spleen: III. Development of innervation in the rat spleen.

The ontogeny of noradrenergic innervation and its compartmental development were studied in the rat spleen using glyoxylic acid histofluorescence and high-performance liquid chromatography (HPLC). Noradrenergic nerves were present at birth in bundles adjacent to the splenic artery and vein. On days 1-3, fluorescent profiles largely were associated with the vasculature and with the perivascular zone. By day 6, these fibers formed increasingly elaborate and tortuous plexuses around the central arteries and their branches. By day 10, fibers were present along the marginal sinus and extended into the developing marginal zone. Between day 10 and day 13 the largest increase in norepinephrine (NE) levels (per mg protein) were noted, and the periarteriolar lymphatic sheath (PALS) achieved its adult form, with increased innervation of the parenchyma. In contrast, the venous/trabecular system developed relatively late. The first trabecular fibers were evident at day 10, and the capsule was not innervated until day 13. From 13 days to adulthood, there was a gradual refinement and extension of existing patterns with no change in NE levels as measured by HPLC (per mg protein), suggesting that the innervation was keeping pace with rapid increases in spleen growth. The pattern of growth and development for noradrenergic nerves in the PALS remarkably parallels changes in T cell compartmentation during this period. We propose that norepinephrine is available for interaction with T cells at the earliest stages of development and could play a role in such processes as lymphocyte packing and the onset of immunocompetence.

Aging↗
PubMed1987

Noradrenergic sympathetic innervation of the spleen: IV. Morphometric analysis in adult and aged F344 rats.

Noradrenergic postganglionic sympathetic innervation of the spleen in 8-month-old (adult) and 27-month-old (aged) Fischer 344 (F344) rats was examined using fluorescence histochemistry for catecholamines coupled with stereologic point-counting analysis for quantitation of noradrenergic varicosities. Noradrenergic varicosities in the spleen were evaluated in four compartments: (1) vascular-, (2) trabecular-, (3) capsular-, and (4) parenchymal-associated fibers. The 27-month-old rats were subdivided further into two groups based upon behavioral testing for gustatory neophobia, a condition reported to be associated with acute locus coeruleus lesions in young rats and with diminished norepinephrine (NE) levels in central noradrenergic neurons in aged rats. In the 8-month-old rats, spleens displayed abundant innervation. Noradrenergic plexuses entered the spleen with the splenic artery and its branches, distributed into capsular and trabecular compartments, and followed the vasculature and trabeculae into splenic white pulp. Noradrenergic fibers entered the white pulp mainly in association with the central artery and its branches; liner and punctate varicosities branched mainly from vascular plexuses into the large, well-defined parenchyma of the white pulp, ending primarily among fields of T lymphocytes. Some fibers extended along the inner edge of the marginal zone and the parafollicular zone. Few noradrenergic varicosities were found in the red pulp. In both groups of aged rats, sympathetic noradrenergic innervation was diminished markedly.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1987

Postnatal development of cell columns and their associated dendritic bundles in the lumbosacral spinal cord of the rat. I. The ventrolateral cell column.

The postnatal development of the ventrolateral dendrite bundle (LDB) in the rat lumbosacral cord was studied quantitatively with Golgi-Cox impregnation. At birth, motoneuronal perikarya and their dendrites were not fully developed, and had not begun to form bundles; varicose dendritic shafts radiated symmetrically from motoneurons. Dendrites contained numerous spines and growth cones. At 5 days, dendritic shafts began to arrange themselves longitudinally, and by 10 days of age, dendrite bundling was apparent. Dendritic growth and bundling appeared complete by two months of age. LDB formation was a dynamic process; rapid dendritic growth occurred in discrete phases with brief intervals of slower dendritic development between them. The mean number of secondary and tertiary dendrites, and the mean branch length of all orders progressively increased. Motoneurons of the LDB primarily innervate the pelvic musculature. Selective horizontal orientation of dendrites into discrete compact bundles suggests that the LDB may serve as a specialized receiving and integrating system for autonomic control over excretory and reproductive functions. It is interesting to note that in patients suffering from amyotrophic lateral sclerosis, motoneurons in the LDB are resistant to destruction. This finding suggests that motoneurons in the LDB may express unique features that protect them from certain disease processes. A better understanding of the developmental anatomical, physiological and biochemical properties of the LDB may provide insight into the treatment of patients with disease processes involving spinal cord and brainstem lower motoneurons.

Animals↗
PubMed1987

Postnatal development of cell columns and their associated dendritic bundles in the lumbosacral spinal cord of the rat. II. The ventromedial cell column.

Postnatal formation of the ventromedial dendrite bundle (MDB) in the rat lumboscral cord was examined quantitatively with Golgi-Cox impregnation. At birth, dendrites of motoneurons in the MDB had not achieved their total length, and had not begun to form bundles. Dendrites projected from the soma in a radially symmetric fashion. At 5 days, dendritic shafts reoriented into the longitudinal plane, and by 10 days of age dendrite bundling was apparent. Between day 1 and 60, primary, secondary and tertiary dendrites from motoneurons in the MDB increased both in number and in length, and the MDB became more compact and intertwined. Dendritic growth and bundling was complete by two months of age. The dendritic spatial arrangement of the MDB, as well as the LDB, may provide an important anatomical substrate for receiving appropriate developing axonal inputs. In turn, it is likely that specific incoming axonal inputs that arrive in this cell column early in development may signal the redirection of dendrites of ventromedial motoneurons into the longitudinal plane.

Animals↗
PubMed1985

Involvement of peripheral and central catecholamine systems in neural-immune interactions.

In this review, we have attempted to delineate the current state of knowledge of the relationships between the immune system and one chemically specific component of the nervous system, the noradrenergic system, both in the brain and the periphery. We have discussed recent work describing the presence of noradrenergic innervation in lymphoid tissues in the major lymphatic organs. Our findings demonstrate clearly that the regions in which lymphocytes (mainly T cells) reside, and through which they recirculate, receive direct sympathetic neural input. The immune system can, therefore, be considered 'hard-wired' to the brain. The evidence for receptors on cells of the immune system capable of receiving signals from the brain is discussed. The significance of this 'hard-wiring' to the function of the immune system is considered, both with regard to the effect of its disruption on immune responses, and to the direct and indirect effects of sympathetic neurotransmitter substances on lymphocytes and their behavior in vitro and in vivo. Finally, our detailed analysis of changes occurring in central noradrenergic pathways as a result of stimulation of the immune system leads to an emerging picture of feedback loops from the immune system to the brain. Such circuits employ endocrine, and probably autonomic, outflow to modulate and regulate immune responses.

Adrenergic Fibers↗